ABSTRACT In the past decade, HIV pre-exposure prophylaxis (PrEP) has demonstrated high HIV protection among at-risk groups, with the first indications that PrEP may be reducing population-level new HIV infections. At the same time, rates of curable sexually transmitted infections (STIs) have increased markedly in populations worldwide, and PrEP-taking populations, including in our preliminary data among African women, have been found to have very high STI rates. Post-exposure prophylaxis (PEP) with the antibiotic doxycycline (dPEP) has been proposed as a novel STI control strategy. A recent open-label clinical trial of dPEP among PrEP-taking men who have sex with men (MSM) in France found a 47% relative reduction in new bacterial STIs (Chlamydia trachomatis, Neisseria gonorrhoeae, or Treponema pallidum), with >70% protection for C. trachomatis and T. pallidum but expectedly no protection for N. gonorrhoeae given high rates of tetracycline resistance in Europe; two new studies of dPEP among MSM are planned for 2019. African women face disproportionate risk from overlapping HIV-STI epidemics, with STI rates comparable to MSM in high-income countries and with consequences (pelvic inflammatory disease, tubal infertility, complications of pregnancy) arguably more severe than those faced by MSM. In contrast to other STI prevention strategies that rely on partner participation, on-demand dPEP would be woman-controlled, and doxycycline has evidence of safety for use by women. We propose to conduct the first study evaluating dPEP to prevent STIs in PrEP-taking African women, who are a priority population for STI prevention, given high risk and engagement in longitudinal prevention services. STI PEP carries substantial potential benefits but also important potential risks, and we have framed our work as capturing key data to inform the risk-benefit calculus for this cutting-edge question. We hypothesize that dPEP will substantially reduce the incidence of curable STIs, particularly C. trachomatis, the most common bacterial STI and the one responsible for greatest morbidity. STI dPEP carries potential risk of antimicrobial resistance, which we have considered: C. trachomatis resistance has never been seen worldwide, making new resistance from dPEP unlikely, but N. gonorrhoeae tetracycline resistance is common in Kenya, and for that reason we hypothesize dPEP may provide little protection for that pathogen but will also not generate new resistance. In addition to resistance risk, data are needed to determine whether dPEP is safe, acceptable, adhered to, and affordable. Aim 1 will determine the benefit of dPEP to reduce the incidence of curable STIs through an open-label 1:1 randomized trial of dPEP versus standard of care among 446 women aged 18-30 taking PrEP. Aim 2 will assess associated risks of dPEP by exploring a) safety, b) acceptability, c) adherence, and d) resistance, using novel and rigorous behavioral and laboratory science methods. Aim 3 will measure the cost of dPEP and estimate the cost per case averted, budget impact, and affordability. If successful, our study will provide the first evidence for an innovative, low-cost strategy to avert substantial morbidity due to curable STIs in this vulnerable, high-risk population.